TRPA1 and Other TRP Channels in Migraine Silvia Benemei*, Francesco De Cesaris, Camilla Fusi, Eleonora Rossi, Chiara Lupi and Pierangelo Geppetti

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REVIEW ARTICLE Open Access TRPA1 and other TRP channels in migraine Silvia Benemei*, Francesco De Cesaris, Camilla Fusi, Eleonora Rossi, Chiara Lupi and Pierangelo Geppetti

Abstract Ever since their identification, interest in the role of transient receptor potential (TRP) channels in health and disease has steadily increased. Robust evidence has underlined the role of TRP channels expressed in a subset of primary sensory neurons of the trigeminal ganglion to promote, by neuronal excitation, nociceptive responses, allodynia and hyperalgesia. In particular, the TRP vanilloid 1 (TRPV1) and the TRP ankyrin 1 (TRPA1) are expressed in nociceptive neurons, which also express the sensory neuropeptides, tachykinins, and calcitonin gene-related peptide (CGRP), which mediate neurogenic inflammatory responses. Of interest, CGRP released from the trigeminovascular network of neurons is currently recognized as a main contributing mechanism of migraine attack. The ability of TRPA1 to sense and to be activated by an unprecedented series of exogenous and endogenous reactive molecules has now been extensively documented. Several of the TRPA1 activators are also known as triggers of migraine attack. Thus, TRP channels, and particularly TRPA1, may be proposed as novel pathways in migraine pathophysiology and as possible new targets for its treatment. Keywords: Migraine; Transient receptor potential ankyrin 1 (TRPA1); Transient receptor potential vanilloid 1 (TRPV1); Calcitonin gene-related peptide (CGRP); Neurogenic inflammation; ThermoTRP; Headache; Pain

Review commonly described as nonselective Ca2+-permeable TRP channels channels, however, their Ca2+/Na+ permeability ratio The observation that the stimulation of a specific receptor, may vary widely between different members of the TRP and the consequent, associated transient inward current family [5]. [1,2] are necessary to vision in Drosophila melanogaster TRP channel gating is operated by both the direct has been the primal evidence of the transient receptor action on the channel of a plethora of exogenous and potential (TRP) family of channels, which currently endogenous physicochemical stimuli, and changes in encompasses more than 50 different channels [3]. TRP the intracellular machinery, including activation of channels represent a heterogeneous system oriented G-protein coupled receptor (GPCR) or tyrosine kinase towards environment perception, and participating in receptor [6]. In mammals, the TRP family consists of sensing visual, gustatory, olfactive, auditive, mechanical, 28 proteins grouped into 6 subfamilies according to thermal, and osmotic stimuli. TRP channels consist of sequence identity, namely TRP canonical (TRPC), TRP six transmembrane domains (S1-S6) with both the NH2 vanilloid (TRPV), TRP melastatin (TRPM), TRP polycystin and COOH termini localized into the cytosol. The COOH (TRPP), TRP mucolipin (TRPML), and TRP ankyrin (TRPA) region is highly conserved among TRPs, whereas the [7,8]. The mammalian TRPC subfamily enlists 7 members NH2 region usually contains different numbers of (TRPC1-7), activated by the stimulation of GPCR and ankyrin repeats, the 33-residue motifs with a conserved receptor tyrosine kinases [9], although TRPC1 seems to be backbone and variable residues that mediate protein- directly activated by membrane stretch [10]. The TRPM protein interactions [4]. The entry of cations through has 8 members (TRPM1-8), and TRPM8 is activated by homo- or heterotetramers occurs via the pore formed menthol and low temperatures (< 25°C). Of the three by loops between the S5 and S6 domains. TRPs are TRPML members, TRPML1 is widely expressed and has been described as an H+-sensor of endosomes/lyso- somes, where it probably prevents overacidification * Correspondence: [email protected] [11]. The TRPP family can be subdivided into PKD1- Headache Center and Clinical Pharmacology Unit, Department of Health Sciences, Careggi University Hospital, University of Florence, viale Pieraccini 6, like (TRPP1-like) and PKD2-like (TRPP2-like) proteins, Florence 50139, Italy

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which couple to act as a signaling complex at the plasma as a sensor of mechanical stimuli and noxious cold (< 17°C) membrane plasma membrane [12]. Various diseases have remains unresolved [36]. Electrophilic molecules have been attributed to mutations of TRP channels. However, been found to activate TRPA1 via auniquemechanism, only a few TRP channelopathies, commonly known as mediated by a Michael addition with specific cysteine “TRPpathies”, have been conclusively identified so far. and lysine residues identified in both the rat and human TRPpathies include neurological disorders, renal diseases, channel [46,47]. Finally, TRPA1-expressing neurons also and complex skeletal dysplasias [13]. express other TRP channels, in particular TRPV1, and, even more importantly, the sensory neuropeptides substance TRPA1 and other thermo-TRPs P (SP), neurokinin A (NKA), and calcitonin gene-related Primary sensory neurons express different TRP channels, peptide (CGRP). SP/NKA and CGRP release from per- including four of the six members of the TRPV subfamily. ipheral endings of nociceptors promoted by TRPV1 or TRPV1, TRPV2, TRPV3, and TRPV4 channels sense TRPA1 activation produces a series of responses col- warm-hot temperatures and are chemosensors for a lectively described as neurogenic inflammation [48]. large series of naturally occurring and synthetic ligands. TRPV1, the receptor of the vanilloid compound capsaicin TRPA1, pain and neurogenic inflammation (which promoted the labeling of the group with the V), It is generally recognized that C and Aδ-fibre sensory is responsive to high proton concentrations (pH 5–6) neurons convey pain signals, while neurons with larger- [14,15], anandamide [16] and various lipid derivatives size fibres mediate touch sensation. Thermo-TRPs, which [17]. Camphor and hypotonic solutions are non-selective under normal conditions are expressed in C and Aδ-fibre activators of the TRPV3 and TRPV4, respectively [18,19]. neurons, have been proposed to contribute to transmis- The synthetic compound 4α-phorbol 12,13-didecanoate sion and modulation of nociceptive signals. This conclu- (4α-PDD), low pH, citrate, endocannabinoids, and ara- sion originates from empirical observation that TRPV1 chidonic acid metabolites may also gate TRPV4 [20,21]. or TRPA1 agonists, derived from foods and spices, are Activators of TRPV2 are not well identified, although able to cause, in a dose-dependent fashion, a range from the uricosuric agent probenecid can activate the channel appreciated hot feelings to unpleasant pain sensation, [22]. Additional TRPs expressed in nociceptors are TRPA1 as in the case of capsaicin, the selective TRPV1 agonist and TRPM8. Finally, there is also evidence that TRPM3, contained in hot peppers, and piperine, another TRPV1 rather uniquely activated by pregnenolone sulfate, seems agonist present in black pepper, or allyl isothiocyanate, to be also expressed in primary sensory neurons [23]. the TRPA1 agonist contained in mustard or wasabi [5,49]. A large NH2-terminal domain with 17 predicted ankyrin Another finding that enlists thermo-TRPs as major pain repeat domains characterizes TRPA1, the sole member controlling mechanisms is the clinical use of topical (cuta- of the TRPA subfamily. TRPA1, first cloned from human neous) capsaicin application that, by defunctionalizing fetal lung fibroblasts, is widely expressed in mammals, sensory nerve terminals, alleviates several pain conditions, where it has been found in hair cells, pancreas, heart, including post-herpetic neuralgias or pain associated with brain, keratinocytes [24], urinary bladder [25], prostate diabetic neuropathy [50]. [26], arteries [27], enterochromaffin cells [28], odonto- Generation of deleted mice and, more importantly, blasts and dental pulp [29,30], synovial fibroblasts [31], identification and preclinical development of selective and epithelial and smooth muscle cells of the airways antagonists for thermo-TRPs, have greatly increased our and lung [32]. A large amount of evidence shows that knowledge of the role of these channels in the regulation TRPA1 plays a key role in the detection of pungent or of acute nociceptive responses and the development of irritant compounds, including principles contained in allodynia and hyperalgesia. While TRPV1-deleted mice different spicy foods, such as allyl isothiocyanate (mustard exhibit decreased hyperalgesia to elevated temperatures oil) in horseradish [33], allicin and diallyldisulfide in [51], TRPA1-deletion abrogated the two classical noci- garlic [34], and cinnamaldehyde in cinnamon [35]. Gingerol ceptive phases to formalin [38]. However, gene deletion (in ginger), eugenol (in cloves), methyl salicylate (in may not completely recapitulate the effects of channel wintergreen), carvacrol (in oregano), thymol (in thyme and blockade, as compensatory mechanism may counterbalance oregano) [36], are also able to gate TRPA1. In addition, the function of the absent gene-protein. Thus, findings environmental irritants and industry pollutants, such as produced by using selective thermo-TRP antagonists acetaldehyde, formalin, hydrogen peroxide, hypochlorite, may better unveil the role of these channels in models isocyanates, ozone, carbon dioxide, ultraviolet light, and of pain diseases. acrolein (a highly reactive α,β-unsatured aldehyde present For detailed information on other thermo-TRPs, the in tear gas, cigarette smoke, smoke from burning vegeta- reader is referred to previous review articles [5-8] whereas tion, and vehicle exhaust), have been recognized as TRPA1 we will focus on the increasing evidence that supports activators [37-45]. The dispute regarding the role of TRPA1 the role of TRPA1 in models of both inflammatory and Benemei et al. The Journal of Headache and Pain 2013, 14:71 Page 3 of 8 http://www.thejournalofheadacheandpain.com/content/14/1/71

neuropathic pain. Mechanical hyperalgesia [52] and ongoing In addition, TRPA1 antagonists could represent novel neuronal discharge [53,54] evoked by complete Freund’s therapeutic strategies of CIPN. In this context, it could adjuvant (CFA) and tumour necrosis factor-α (TNFα), be better understood that the unexpected attenuation and mechanical hyperalgesia induced by low doses of by etodolac, a nonsteroidal anti-inflammatory drug of monosodium iodoacetate (MIA) [55] are inhibited by mechanical allodynia in a mouse model of neuropathic TRPA1 receptor antagonists in rodents. Convergent find- pain, might be due to its ability to inhibit TRPA1 [67]. ings indicate that TRPA1 contributes to carrageenan- In addition, to contribute to mechanical hyperalgesia, evoked inflammatory hyperalgesia [56,57]. Carrageenan TRPA1 seems to be involved in the development of cold administration, among a number of lipid derivatives, allodynia [68]. Cold allodynia was reduced in models of notably increases metabolites of 12-lipoxygenases, par- neuropathic (peripheral nerve injury) and inflammatory ticularly hepoxilins A3 (HXA3) and HXB3, whose hyper- (CFA) pain [69,70] or in models of CIPN, which typically algesic/allodynic effect is abrogated by TRPA1 antagonism exhibit this type of hypersensitivity [64-66]. Interestingly, [58]. It has also been found that TRPA1 mediates ongoing a familial episodic pain syndrome has been attributed nociception in chronic pancreatitis [59], and that both toagainoffunctionmutationofTRPA1TRPA1[71]. TRPV1 and TRPA1 initiate key pathways to transform Coincidence between TRPA1 and neuropeptide expres- acute into chronic inflammation and hyperalgesia in sion has been suggested [72,73], although evidence for pancreatitis [60]. The clinical observation that an anti- coexistence of isolectin B4-positive and non-peptidergic oxidant afforded protection in patients with pancreatitis neurons with TRPA1 has also been reported [74,75]. [61] indirectly supports the role of the oxidative stress Notwithstanding, exposure of tissues containing either sensor, TRPA1, in this condition. peripheral or central sensory nerve terminals to TRPA1 The underlying mechanisms that from neural tissue agonists invariably results in a calcium-dependent release injury produce the chronic allodynia and hyperalgesia of SP/NKA and CGRP. Thus, TRPA1 stimulation has been typical of neuropathic pain are largely unknown. How- proven to increase sensory neuropeptide release from ever, recent reports have pointed to the role of TRPA1 oesophagus and urinary bladder, meninges, or dorsal in different models of neuropathic pain. Several meta- spinal cord [76-78]. The outcome of such a release in bolic pathways in glycolysis or lipid peroxidation pro- peripheral tissues encompasses the series of responses duce methylglyoxal (MG), which appears in the plasma commonly referred to as ‘neurogenic inflammation’ [48] in diabetic patients as hyperglycemia strongly enhances (Figure 1). Although implication in transmission of noci- MG accumulation. MG has been recently described to ceptive signals has been proposed, the pathophysiological react reversibly with cysteine residues, and probably due outcome of the central release of sensory neuropeptides to this property stimulates TRPA1, thus representing a within the dorsal spinal cord or brain stem is less clear likely candidate metabolite to promote neuropathic pain (Figure 1). in metabolic disorders [62]. Chemotherapeutic induced peripheral neuropathy (CIPN) is a scarcely understood TRPA1, TRPV1, and migraine and poorly treated condition, which, characterized by One of the first findings that, although indirectly, sug- spontaneous pain, and mechanical and cold allodynia and gested the role of TRP channels in cluster headache and hyperalgesia, causes significant discomfort, and often migraine was represented by the protective effect of the therapy discontinuation. CIPN may outlast the time topical, desensitizing application of capsaicin to the pa- period of chemotherapeutic drug administration for weeks tient nasal mucosa [79,80]. Capsaicin treatment couples or months [63]. the unique ability of the drug to first activate, and, Alteration of several ion channels has been advocated subsequently, upon repeated administration, desensitize to explain this painful condition, but a univocal consensus both the afferent pathway that from channel activation has not emerged. Recently, in mouse models of CIPN conveys nociceptive signals, and the ‘efferent’ function produced by a single administration of oxaliplatin, pac- that results in sensory neuropeptide release [48]. Within litaxel or bortezomib, TRPA1 has been shown to play a the fifth cranial nerve, capsaicin desensitization causes major role in the development and maintenance of cold the defunctionalization of peripheral and possibly central and mechanical [64-66]. In a therapeutic perspective, it nerve endings, thus preventing SP/NKA-dependent plasma is of relevance that treatment with a TRPA1 antagonist protein extravasation within the dura mater, CGRP- just before and shortly after (about 6 hours) the admin- dependent dilatation of meningeal arterioles, and inhib- istration of bortezomib or oxaliplatin totally prevented ition of afferent nociceptive impulses. Further support the development and maintenance (for 10–15 days) of to the contribution of TRPV1 to migraine mechanism mechanical and cold hypersensitivity [66]. This finding derived from the observation that ethanol, a known suggests that TRPA1 is key in initiating CIPN and promot- trigger of migraine attacks, activates CGRP release from ing the transition from an acute to a chronic condition. sensory neurons, and promotes CGRP-dependent menin- Benemei et al. The Journal of Headache and Pain 2013, 14:71 Page 4 of 8 http://www.thejournalofheadacheandpain.com/content/14/1/71

Figure 1 Schematic representation of the probable mechanisms of the action of antimigraine remedies, either currently used, or proven effective in clinical trials (gray boxes) or of novel medicines (empty box), regarding their ability to modulate the release of calcitonin gene related peptide (CGRP) or the activation of its receptor (CGRP-R). (1) Non steroidal antiinflammatory drugs (NSAIDs) block prostaglandin synthesis and the ensuing nociceptor sensitization and CGRP release evoked by prostaglandin receptor (PG-R) activation. (2)

Triptans, by activating neuronal 5HT1D receptors, inhibit CGRP release. (3) CGRP-R antagonists inhibit the action of CGRP on effector cells. (4) Antagonists of transient receptor potential channels (TRPs), including TRP ankyrin 1 (TRPA1), block the ability of a series of stimulants (for TRPA1, cigarette smoke, acrolein, nitric oxide, umbellulone, and others) to release CGRP. All medicines may act at both peripheral and central endings of trigeminal nociceptors. Receptor/channel activation may trigger/facilitate (+) or inhibit (−) CGRP release. geal vasodilatation by reducing the threshold temperature only 5–6 hours after nitroglycerine administration [92,93]. for channel activation, a phenomenon that eventually Although not confirmed in vitro [94]. NO may release results in TRPV1 activation [81,82]. CGRP from trigemino-vascular neurons [95]. More TRPV4 is stimulated by hypoosmotic stimuli that cause recently, NO has been revealed to target TRPA1 by plasma membrane stretch and mechanical distension. nitrosylation of channel cysteine residues [96], that Although this effect could, in principle, be implicated seem to differ from those targeted by other reactive in the throbbing pain often described by migraine patients molecules [97], and this novel molecular mechanism during their headache attacks, no evidence has yet been could contribute to the nociceptive response evoked by reported in support of TRPV4 in any model of head pain. NO [98]. It is possible that the S-nitrosylation process In contrast, a series of observational findings has recently [99], produced by NO, contributes to channel sensitization been obtained regarding a possible association between to eventually (hours after the exposure to NO) amplify TRPA1 and migraine. In this respect, it is of interest CGRP release by other agents, thus leading to exagger- that a number of compounds, recently identified as TRPA1 ated neurogenic inflammation and potentiation of pain agonists, including cigarette smoke, ammonium chloride, responses. formaldehyde, chlorine, garlic and others [34,38,41,78,83] The environmental pollution agent, acrolein, is pro- are known triggers of migraine attacks in susceptible duced by the combustion of organic material which causes individuals [84-89]. its accidental inhalation, which, however, occurs also with Nitric oxide (NO) donor drugs, including nitroglycerine, cigarette smoking [100]. Several components of cigarette are known inducers of migraine attacks and have been smoke, such as acrolein, crotonaldehyde [78], acetaldehyde extensively used in migraine provocation studies in [37] and nicotine [101], are TRPA1 agonists. Recently, humans [90]. Although their pro-migraine action has acrolein application to the rat nasal mucosa has been been attributed to their intrinsic vasodilatatory action shown to produce ipsilateral meningeal vasodilatation [91], the temporal mismatch between vasodilatation by a TRPA1- and CGRP-dependent mechanism [102], and the onset of migraine-like attacks argues against a thus offering a mechanistic explanation for the association close association between the two phenomena. In fact, between the exposure to cigarette smoke and migraine at the time of the maximum vasodilatation, a mild to attack appearance or worsening [103,104]. moderate headache develops both in migraineurs (more) Herbalism has been instrumental for the development and in healthy subjects (less), while delayed migraine-like of pharmacology and also to a better understanding of attacks, present only in migraine patients, are observed pathophysiological mechanisms. These principles also Benemei et al. The Journal of Headache and Pain 2013, 14:71 Page 5 of 8 http://www.thejournalofheadacheandpain.com/content/14/1/71

apply to the migraine field. Umbellularia californica graine, as compared to pain‐free state, and that topical (California bay laurel) is also known as the ‘headache application of inflammatory molecules on the rat menin- tree’ because of the ability of its scent to trigger headache ges sensitizes thalamic trigeminovascular neurons [112]. attacks in susceptible individuals [105]. A case of cluster Each component of the nociceptive pathways could con- headache-like attacks preceded by cold sensations per- tribute differently to sensitization of the neural tissues. ceived in the ipsilateral nostril following inhalation of TRP channels could be sensitized by different compounds Umbellularia californica scent has recently been described and via different mechanisms [5,36,66,81,113]. Although in a cluster headache patient whose attacks had ceased there is no specific information on the role of these chan- 10 years before [106]. The irritant monoterpene ketone, nels to peripheral nociceptor sensitization or central sensi- umbellulone, one of the most abundant reactive mole- tization in migraine, it is possible that TRP channels, and cules of Umbellularia californica, was found to activate in particular TRPV1 and TRPA1, contribute to this key the human recombinant and the constitutive rat/mouse mechanism. TRPA1 in trigeminal ganglia (TG) neurons, and via this mechanism to produce nociceptive behaviour and the Conclusions release of CGRP from TG or meningeal tissue in rats [77]. The still largely unfinished puzzle of the migraine mech- In addition, similar to acrolein, umbellulone application anism is being completed by novel unexpected pieces of to the rat nasal mucosa evoked ipsilateral TRPA1- and information, which compose a clearer picture. The first, CGRP-dependent meningeal vasodilatation [77]. corner of the picture, known for decades, is that cyclo- Ligustilide, an electrophilic volatile dihydrophthalide of oxygenase (namely cyclooxygenase 2) inhibition has a dietary and medicinal relevance, has been found to beneficial effect on migraine attack. The second corner, produce a moderate activation of TRPA1, but also to predicted by scientists and appreciated by clinicians and inhibit allyl isothiocyanate-evoked stimulation of TRPA1 patients, is that targeting 5-HT1 receptors is also highly [107]. This newly identified target of ligustilide offers a effective. The third corner is that a series of clinical trials novel mechanistic explanation for the use of the compound show that CGRP antagonists afford a protection similar in traditional medicine to treat pain diseases, including to that of triptans. To complete at least the frame, a headaches. Finally, although several hypotheses have fourth corner, which should reconcile the other three in been advanced, the mechanism of the analgesic action of an intelligible sequence of events, is needed. While pros- acetaminophen (paracetamol) in different pain conditions taglandins sensitize nociceptors and eventually promote is far from clear. The reactive metabolite of acetamino- CGRP release, triptans inhibit such release, thus produ- phen, N-acetyl-p-benzo-quinoneimine (NAPQI), is able to cing an indirect anti-migraine effect, and CGRP antago- activate the TRPA1 channel and thereby evoke a moderate nists abrogate the final common pathway of migraine and reversible neurogenic inflammatory response, which, mechanism. The pathway, which, sensitized by prosta- in susceptible individuals, may contribute to emphasizing glandins and inhibited by serotonin receptor stimulation, inflammation in peripheral tissues [76]. However, NAPQI results in trigeminal neuron activation and the pro- may also be produced by cytochrome activity within migraine release of CGRP could represent the fourth the spinal cord, and NAPQI action at the spinal level corner of the picture. Emerging information on TRP chan- results in channel desensitization [108]. Inhibition of nels, and particularly TRPA1, which, targeted by migraine central TRPA1 has been advocated as the mechanism, triggers, contribute, by activating the trigeminal CGRP- which may be responsible the hitherto unexplained an- dependent pathway, to the genesis of pain and the accom- algesic and possibly antimigraine action of its parent panying symptoms of the attack, seems to be of paramount molecule [108]. Importantly, this novel spinal mechanism importance to solve what still remains the enigma of the could be of general relevance also for other TRPA1 migraine mechanism. agonists which share with NAPQI the ability of desensitizing the channel. Competing interests A host of endogenous inflammatory mediators possibly The authors declare that they have no competing interests. released during migraine attacks can activate and sensitize peripheral and central sensory neurons, including tri- Authors’ contribution geminal neurons. Sensitization of first-order neurons is FDC, CF, ER, and CL searched for the literature. SB and PG wrote and revised involved in the perception of headache throbbing pain the text. All authors read and approved the final manuscript. [109], while sensitization of second‐order neurons contributes to cephalic allodynia and muscle tenderness Acknowledgements [110,111]. Recently, it has been shown that innocuous We acknowledge Regione Toscana (Regional Health Research Program 2009, P.G.). brush and heat stimuli induce larger activation in the Received: 22 May 2013 Accepted: 10 August 2013 thalamus of patients who exhibit allodynia during mi- Published: 13 August 2013 Benemei et al. The Journal of Headache and Pain 2013, 14:71 Page 6 of 8 http://www.thejournalofheadacheandpain.com/content/14/1/71

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